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Ann Surg. 2018 Oct 17. doi: 10.1097/SLA.0000000000003022. [Epub ahead of print]

Genetic Analysis of Small Well-differentiated Pancreatic Neuroendocrine Tumors Identifies Subgroups With Differing Risks of Liver Metastases.

Author information

1
Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD.
2
Department of Surgery, The Pancreas Institute, Verona, Italy.
3
Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD.
4
Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD.
5
Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.
6
Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
7
Department of Pathology, Pederzoli Hospital, Peschiera, Italy.
8
Department of Surgery, Pederzoli Hospital, Peschiera, Italy.
9
ARC-Net Applied Research on Cancer Center, University and Hospital Trust of Verona, Verona, Italy.

Abstract

OBJECTIVE::

The aim of this study was to investigate the key molecular alterations in small primary pancreatic neuroendocrine tumors (PanNETs) associated with the development of liver metastases.

BACKGROUND:

Well-differentiated PanNETs with small size are typically indolent; however, a limited subset metastasize to the liver.

METHODS:

A total of 87 small primary PanNETs (<3 cm), including 32 metastatic cases and 55 nonmetastatic cases after a 5-year follow-up, were immunolabeled for DAXX/ATRX and analyzed for alternative lengthening of telomeres (ALT) by Fluorescence In Situ Hybridization. A subset of these cases, 24 that metastasized and 24 that did not metastasize, were assessed by targeted next-generation sequencing and whole-genome copy number variation.

RESULTS:

In the entire cohort, high Ki-67 (OR 1.369; 95% CI 1.121-1.673; P = 0.002), N-stage (OR 4.568; 95% CI 1.458-14.312; P = 0.009), and ALT-positivity (OR 3.486; 95% CI 1.093-11.115; P = 0.035) were independently associated with liver metastases. In the subset assessed by next-generation sequencing and copy number variation analysis, 3 molecular subtypes with differing risks of liver metastases were identified. Group 1 (n = 15; 73% metastasized) was characterized by recurrent chromosomal gains, CN-LOH, DAXX mutations, and ALT-positivity. Group 2 (n = 19; 42% metastasized, including 5 G1 tumors) was characterized by limited copy number alterations and mutations. Group 3 (n = 14; 35% metastasized) were defined by chromosome 11 loss.

CONCLUSIONS:

We identified genomic patterns of small PanNETs associated with a different risk for liver metastases. Molecular alterations, such as DAXX mutations, chromosomal gains, and ALT, are associated with an increased risk of metastasis in small PanNETs. Therefore, targeted sequencing and/or ALT analysis may help in the clinical decisions for these small PanNETs.

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